Endometrial Cancer

1. Management

What therapies should you initiate immediately (i.e., emergently)?

If adjuvant therapy is indicated, there is no need to initiate any treatment immediately. Sufficient time for patient recuperation is appropriate. Therapy is typically begun within 6 weeks of surgery.

What should the initial definitive therapy for the cancer be?

Total hysterectomy and bilateral salpingo-oophorectomy, preferably laparoscopically as supported by prospective data, should be performed in any patient for whom surgery is possible. Surgical evaluation of lymph nodes remains controversial. Our practices vary; some surgeons perform nodal sampling or lymphadenectomy in all patients with endometrial cancer ,whereas others omit nodal evaluation in patients with disease confined to the endometrium on intraoperative assessment with extent of nodal evaluation varying based on depth of myometrial invasion.

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Pathologic examination provides two key pieces of information that identify patients in need of adjuvant therapy. First, it identifies if the tumor is type I (typically lower grade lesions arising in a background of hyperplasia, confined to the uterus, and comprising the vast majority of endometrial cancer) or type II (higher grade lesions or high-risk histologies that arise in a background of atrophy that have a greater tendency for extrauterine spread). Second, pathologic examination provides characteristics used to classify the tumor as low, intermediate, or high risk. A number of histopathologic characteristics are associated with increased risk of metastasis and recurrence. These factors include grade, depth of myoinvasion, extrauterine spread, histology, lymphovascular space involvement, and tumor size. Additionally, older age may be independently associated with worse prognosis. Assessment of these characteristics allows risk stratification identifying patients most likely to benefit from adjuvant treatment.

Low-risk endometrial cancer includes type I tumors confined to the endometrium. Intermediate risk tumors are those confined to the uterus with myometrial invasion. Gynecologic Oncology Group (GOG) 99 defined “high-intermediate risk” as those patients with outer third myometrial invasion, lymphovascular invasion and grade 2-3; age 50 to 69 with any two risk factors; age greater than 70 with any risk factor. Those with myometrial invasion but not meeting this definition can be considered low-intermediate risk. We consider high-risk stage I disease to be all type II tumors confined to the uterus.

Primary radiation is an option; however, it should be employed only for patients at unacceptable risk from surgery. There are few case series describing outcomes, and still fewer that used high-dose rate (HDR) radiation, which is becoming commonplace. Niazi et al. reported 38 medically inoperable patients (29 clinical Stage I, 9 Stage II) treated with HDR brachytherapy (BT) with or without external beam radiation (EBRT). Eleven patients (29%) recurred (6 local, 4 distant, 1 both). The 15-year disease specific survival rate was 78% for stage I patients and 42% for Stage II; however, 15 patients died of unrelated causes. Another series of 29 patients with medically inoperable stage I, II, and III (48%, 31%, and 21%, respectively) disease were treated with EBRT and HDR-BT. At nearly 5 years, 6 patients were alive without disease, 8 died of disease, and the remainder died of unrelated causes. We counsel patients that primary RT is appropriate only for those who cannot undergo surgery as primary RT offers inferior survival rates.

Early stage, type I

Low risk: GOG 33 reported no recurrences in grade 1-2 lesions without myometrial invasion regardless of receiving radiation or not. Those with high-grade tumors were rare, but 1 out of 5 observed patients recurred versus 0 out of 3 radiated patients. Adjuvant therapy is typically withheld in these patients.

Low-intermediate risk: GOG 33 included 169 low-intermediate risk patients and found nearly identical risk of recurrence among patients treated with adjuvant radiation versus those receiving none. The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial found that the most advanced of this group (superficially invasive, grade 2 lesions) had a less than 5% chance of recurrence (in a population largely unstaged), and therefore advised against adjuvant radiation in these cases.

PORTEC, GOG 33, and ASTEC/EN.5, focusing largely on intermediate-risk disease, are fairly uniform in demonstrating a decrease in local recurrence with adjuvant RT while not prolonging overall survival. The benefits in the low-intermediate risk group are minimal and do not appear to outweigh the potential side effects of adjuvant therapy.

Those at highest risk are patients younger than 50 with deep invasion of a well-differentiated tumor (i.e., those not meeting the definition of high-intermediate risk). This is a rare; only 18 of 621 patients in GOG 33 were found to have outer one third myometrial invasion of a grade 1 tumor. All 10 followed for recurrence were treated with RT and 1 recurred. PORTEC data suggests locoregional recurrence of these patients is similar to poorly differentiated tumors with superficial invasion (i.e., approximately 10%). However, strong consideration should be given to including EBRT if lymphadenectomy was not performed as the risk of pelvic node involvement is approximately 11%.

1. Radiotherapy

In the PORTEC trial, 72% of patients were older than 60 years of age, 80% had grade 2 or 3 histology, and the majority had outer half myometrial invasion. A hazard ratio of 3.9 (CI 2.0-7.6) for locoregional recurrence was reported in the group not receiving radiation, but no difference in survival time was identified at 5 years. In reporting their 10-year data, there was a persistent effect on locoregional recurrence but no effect on survival time for patients meeting the GOG 99 definition for high-intermediate risk disease. The major benefit of radiation therapy for this group appears to be in locoregional control.

PORTEC-2 enrolled women more than 60 years old with a combination of high-intermediate-risk disease; the bulk of these were outer half myometrial invasion with grade 1-2 tumors. The patients were randomized to EBRT or BT. At the 45-month median follow-up, the only difference between the 2 groups was in the rate of pelvic recurrences (0.5% in EBRT vs. 3.8% in VBT, P = .02), which did not persist once a centralized pathology review was performed. We advocate VBT to be the adjuvant therapy of choice in patients at high-intermediate risk of recurrence.

2. Chemotherapy

Maggi et al. conducted a trial in 345 patients with outer half invasion, cervical involvement, or Stage III disease; approximately one third of the patients were Stage I/II, though node assessment was not mandated. The group was randomized to receive radiation or cyclophosphamide/Adriamycin/cisplatin (CAP). There was no difference between the two treatment groups in terms of recurrence or survival. However, the data suggested increased local control in the radiation group and better prevention of distant metastases in the chemotherapy group.

Susumu et al reported the results of the Japanese GOG Trial 2033. Three hundred eighty-five patients with deep half invasion of Stage I-III disease were randomized to pelvic radiotherapy or CAP chemotherapy. Approximately three fourths of the cases were stages I and II, and nearly all underwent pelvic node dissection. The recurrence rates and patterns were similar between the two groups. Subgroup analysis showed that the 120 patients with outer half myometrial invasion, over age 70 or with grade 3 disease, and Stage II or IIIA patients with deep half myometrial invasion, had a statistically significant improvement in progression free survival (PFS) and overall survival (OS) from chemotherapy (83.8% vs. 66.2%, P = .024 and 89.7% vs. 73.6%, P = .006, respectively).

A Surveillance, Epidemiology, and End Results (SEER) database review and a meta-analysis have suggested a survival advantage with radiation for deep myometrial invasion. The NSGO-EC-9501/EORTC-55991 study sought to examine the utility of RT + CT (chemotherapy, mostly Adriamycin/cisplatin) vs. RT only in Stage I, II, and IIIA/C patients. Little more than half of the 378 randomized patients had deep myometrial invasion or cervical involvement, and around 60% were endometrioid histology. There was improvement in PFS and disease-specific survival (DSS) in the CT + RT group (HR 0.64 [CI 0.41-0.99] and 0.51 [0.28-0.90], respectively) that persisted in the endometrioid histology only group (HR 0.50 [CI 0.27-0.95] and 0.42 [CI 0.19-0.93], respectively). These results were not stratified by stage.

RTOG 9708 was a phase II study treating this population with chemoradiation (45 Gy EBRT over 5 weeks followed by 18-20 Gy brachytherapy with cisplatin 50 mg/m 2 on days 1 and 28) followed by paclitaxel 175 mg/m 2 and cisplatin 50 mg/m 2 for four cycles in patients with deep myometrial invasion of a grade 2-3 tumor or a more invasive lesion. Forty-four patients were followed to a median follow-up of over 4 years, with more than 90% compliance to the protocol. Seventeen patients were Stage I/II, and there were no recurrences in this group.

GOG 249 hopes to clarify utility of adding chemotherapy to radiation, and PORTEC 3 is examining the role of chemoradiation. Currently, radiation decreases local recurrence without obvious effect on survival; there may be an emerging utility of chemotherapy or multimodal therapy for those at high risk of recurrence, but there is not strong data upon which to recommend chemotherapy.

Early stage, type II

Serous carcinoma

Uterine papillary serous carcinoma (UPSC) represents 10% to 22% of endometrial cancers and 39% of endometrial cancer deaths. One third to two thirds of patients without myometrial invasion will be found to have extrauterine disease upon comprehensive surgical staging. Approximately half of serous carcinomas are diagnosed as Stage I tumors, but the 5-year survival rate in this setting is 50% to 80%. Recurrence is usually outside the pelvis, often in multiple sites. Stage, lymphovascular space invasion, pure versus mixed tumors, and tumor size do not necessarily correlate with risk of recurrence.

Prospective GOG data reported PFS of 38.1% at 5 years for Stage I and II disease that was treated with whole abdominal irradiation (WAI), leading the authors to advocate use of alternative adjuvant therapies. A series of 60 patients with surgical stage I UPSC reported outcomes for the one third who received adjuvant therapy and the remainder who did not. Twelve received some form of RT and two of those recurred at a mean 40-month follow-up; both were outside the pelvis and both died of disease. Seven received platinum-based chemotherapy, and none had recurred at 32 months of follow-up. An additional patient was treated with chemotherapy and WAI who was disease free at nearly 5 years. The mean follow-up in the observation group was 24 months, with 17.5% recurring, half outside the pelvis, and all died of disease. A second series of 206 women with Stage I or II disease reported recurrence of 31% for observation, 38% for radiation alone, and 11% for adjuvant therapy including chemotherapy.

Fader et al reported 142 surgical stage I UPSC patients. Thirty-three received no adjuvant treatment, 20 radiation alone, and 89 chemotherapy (platinum/taxane) with or without RT (33 and 56, respectively). At median follow-up of 37 months, there were 25 recurrences (17.6%), 15 outside the pelvis. The CT arm had a reduction of recurrence versus the remainder of the group (11.2% vs. 28.3%, P = .013). The recurrence rates for observation, RT, and CT for endometrial-confined disease were 15.8%, 20%, and 7.4%, respectively; these were not statistically significant. The addition of RT to CT did not improve recurrence versus CT alone. None of the three patients lacking residual disease in the hysterectomy specimen recurred.

Another series of 74 patients with surgical stage I UPSC reported outcomes according to presence or absence of disease in the uterus at the time of surgery. Of the 12 patients without residual disease, 3 received adjuvant therapy and 9 received none; there were no recurrences. There were 21 patients with endometrial-confined disease with residual disease, of whom 7 received chemotherapy and 14 did not. Forty-three percent of the latter group recurred versus none in the former, resulting in a statistically significant improvement in overall survival and progression-free survival. Upon multivariate analysis, substage was found to be a statistically significant predictor of recurrence.

Fifty-five surgical Stage II patients were reported with median follow-up of 33 months. Recurrence rates were 50% for observed patients and those that received RT only, whereas it was 10.5% for CT with or without RT. Furthermore, 70% of recurrences were outside the pelvis; the six with recurrence in the pelvis only had not received CT. There were no recurrences in those treated with CT in addition to RT. Fields et al reported phase 2 data in 30 patients, 18 of whom were stage I/II. They received six cycles of paclitaxel/platinum with EBRT and VBT “sandwiched” between cycles three and four. Grade 3/4 neutropenia occurred in 42%, but only six cycles of CT were delayed a week. Twelve of the early stage patients were alive at 3 years. At any stage, patients with UPSC benefit from chemotherapy, with the possible exception of those without a tumor in the hysterectomy specimen.

Clear cell carcinoma

Uterine clear cell carcinoma (UCCC) is rarer than UPSC, accounting for 1% to 6% of all endometrial cancer diagnoses. A retrospective review of 99 patients revealed that approximately 50% of patients present with stage I/II disease, and that upon comprehensive surgical staging, 52% of women with presumed disease confined to the uterus will be upstaged.

Prospective studies of radiotherapy specifically in clear cell carcinoma are lacking. The most robust is the GOG prospective report of 13 patients treated with RT. Six of these patients died, at least four of disease. A retrospective record review of 5,747 patients treated at the Norwegian Radium Hospital between 1970 and 1992 revealed that of 181 patients with clear cell carcinoma, 96 were pathologic stage I and 58 recurred. There were 16 patients who did not receive RT in the group; assuming all were Stage I, the recurrence rate was still over 25%.

A review of 49 patients with Stage I/II UCCC (22 receiving systematic lymphadenectomy and the remainder none or suboptimal dissection) reported half of the former received adjuvant therapy (7 radiation, 2 chemotherapy, 2 both) and half none; there was one failure in the lymphadenectomy group. Nine of the remaining 27 patients recurred; 5 received no adjuvant therapy. The authors’ conclusion was that surgical stage I UCCC may not require adjuvant therapy, although in this small group of nine patients the recurrence rate was still 11%.

Serous carcinoma present in the hysterectomy specimen requires strong consideration of chemotherapy with addition of RT a reasonable plan as well. Experience with early UCCC carcinoma is limited; our strategy is treating it similarly to serous carcinoma.

Carcinosarcoma

Uterine carcinosarcoma accounts for less than 5% of uterine malignancies. Approximately 60% of these tumors will present with extrauterine disease, and the 5-year survival rate for a Stage I tumor is less than 50%. Adjuvant therapy in even the earliest cases is necessary. Thirty surgical Stage I and eight Stage II patients were reported with regards to adjuvant therapy after surgery; approximately half underwent node sampling. Half the 10 patients treated with surgery alone recurred in the pelvis versus 21% of those treated with pelvic radiation (P = .09). Approximately 40% of each group recurred outside the radiation field. Only 1 patient had an isolated pelvic recurrence. The estimated 5-year survival rates were similar between the two groups.

Data from EORTC protocol 55874, which randomized 92 stage I or II carcinosarcoma patients to radiotherapy or observation, showed no difference in survival time or rate of distant metastases, but there was a trend toward improved local control (24% local recurrence in radiotherapy group vs. 47% in the observation group). Using SEER data, a cohort of 1,819 women with stage I/II carcinosarcoma was identified, 37% of whom were treated with radiation. The HR for cancer-specific survival rate was 0.79 (CI 0.69-0.91) favoring RT. On subgroup analysis, only those not surgically staged benefitted from radiation implying improved local control for early-stage carcinosarcoma from radiation, and perhaps a survival advantage in unstaged patients. There is SEER data implying therapeutic benefit to lymphadenectomy in this disease.

COG 150 included 90 women with stage I/II disease as part of 206 randomized to whole abdominal radiation or cisplatin/ ifosfamide/mesna for three cycles. The results were not stratified by stage, there was no difference in survival or recurrence between the two groups. The adjusted RR of recurrence for the chemotherapy group was 0.789 (P = .245) and death 0.712 (P = .085).

GOG 108 reported no survival advantage but a small progression free survival advantage for adding cisplatin to ifosfamide. However, GOG 161, which compared ifosfamide (2 g/m 2 days 1 to 3, every 21 days for 8 cycles) and ifosfamide (1.6 g/m 2 days 1 to 3) with paclitaxel (135 mg/m 2 over 3 hours) every 21 days in advanced stage patients, showed significant an advantage to combination chemotherapy in terms of progression free survival, decrease in risk of progression or death (RR 0.71, P = .03), and in overall survival (RR 0.69, P = .03). This trial did not include early-stage patients, but the regimen has become standard adjuvant therapy by extrapolation. There is currently a trial in all stages of this regimen versus carboplatin/Taxol, which has shown activity in this disease.

Multimodality therapy has been employed increasingly. A pilot study of 38 patients with stage I/II carcinosarcoma was conducted in which patients were treated with external radiotherapy (or brachytherapy alone if lymphadenectomy was performed and negative) sandwiched between two cycles of cisplatin/epirubicin and an additional two cycles if Stage I or four cycles if Stage II. Twenty-one patients were Stage I/II. Sixty-one percent received platinum/epirubicin, but 29% received no chemotherapy at all for various reasons. In all, 55% (21 of 38) received the protocol as planned. The overall survival rate in the multimodality group was 95% and disease-free survival rate was 90% at median follow-up of 58 months. This compares favorably to those who did not complete the protocol, who had an overall survival rate of 47% at approximately 4 years.

A second report examined pooled patients from three hospitals, each of which had a unique preferred adjuvant therapy (radiation, chemotherapy, or multimodality treatment). Sixty-five percent of the 49 included patients were Stage I/II and 96% underwent surgical staging. Chemotherapy consisted of ifosfamide 1500 mg/m 2 per day x 5 days plus Mesna and cisplatin 60 mg/m 2 days 1,21 for six cycles if used alone, or Ifosfamide 1200 mg/m 2 per day x 3 days with Mesna and cisplatin 80 mg/m 2 on day 3 for three cycles if used as part of sequential therapy. Survival rate was highest for the multimodality group (75% at 5 years), significantly longer than those receiving only chemotherapy (22.2%, P = .05) and nonsignificant versus radiotherapy alone (50.5%).

Adjuvant therapy for carcinosarcoma should consist of at least chemotherapy, with ifosfamide/paclitaxel being the most active regimen. Strong consideration should be given to the addition of radiation, especially in those who were not surgically staged.

Stage III and IV, all histotypes

Adjuvant chemotherapy

GOG 122 randomized 388 optimally debulked, surgical stage III/IV endometrial cancer patients to WAI or chemotherapy with Adriamycin (60 mg/m 2)/cisplatin (50 mg/m 2) every 21 days for eight courses, the last consisting of cisplatin alone (AP). Only 63% of the chemotherapy group completed treatment. There was a significant improvement in PFS (HR 0.71, CI 0.55-0.91) and OS (HR 0.68, CI 0.52-0.89), with higher incidence of pelvic recurrence in the chemotherapy group and less abdominal/distant recurrence. Adverse events were markedly higher in the chemotherapy group with 85% experiencing grade 3-4 neutropenia. Quality of life studies from these data suggest a significant impact on the chemotherapy group, especially in terms of peripheral neuropathy.

The effect was not robust with the addition of EBRT, as GOG 184 randomized 552 women to receive pelvic RT (or extended field radiation therapy [EFRT] if positive or inadequately sampled paraaortic nodes) followed by either AP or TAP. Approximately 60% of each group was alive at 3 years of follow-up with no difference in recurrence. There was more myelosuppression and neuropathy in the TAP arm. However, the subgroups of women with gross residual disease and those prescribed EFRT who did not receive it, benefited from a significant improvement in recurrence-free survival.

While TAP probably represents the GOG standard, carboplatin/paclitaxel represents the community standard due to the vast experience and much better tolerability of the regimen. It has not been validated in phase III trials, but efficacy appears to be present from several smaller retrospective and phase II studies, which have reported response rates of 40% to 78%GOG 209 should provide more definitive data on the subject.

Retrospective analysis of 356 patients with Stage III/IV disease was reported with respect to adjuvant therapy received (approximately one half radiation and one fourth each chemotherapy and multimodality treatment). The chemotherapy group was older, with a larger number of high-risk histotypes and suboptimally debulked disease. After controlling for these, the HR for overall survival was 1.60 for chemotherapy alone (NS) and 2.01 for radiation alone (P = .012) in favor of multimodal therapy. Considering only optimally debulked patients, there was a statistically significant advantage for multimodality therapy over the other two groups in terms of disease progression and overall survival. A subgroup analysis was performed examining those receiving “sandwich therapy” versus those receiving the entirety of one modality before the other. This showed a significant advantage of “sandwich therapy” in terms of 3-year overall survival rate and progression-free survival rate.

Likewise an expanded cohort of 109 patients with Stage III/IV disease was examined to define the optimal sequence of chemotherapy (mostly carboplatin and paclitaxel) and radiation. Forty-one percent received sandwich therapy. Overall survival rate and progression-free survival rate was improved for the sandwich group (OS HR 5.74 [CI 1.96-16.77] for radiation/chemo and 2.6 [CI 1.01-6.71] for chemo/radiation), which was robust when considering only those optimally debulked. Sandwich therapy patients had less neutropenia and similar rates of radiation complications.Sandwich therapy appears tolerable and likely more effective than either modality in isolation. It should be considered in all women with intraperitoneal spread of endometrial cancer. If disease is purely intraperitoneal, omission of radiation is reasonable.

Hormonal therapy: Current evidence does not support the use of adjuvant treatment of advanced endometrial cancer with any hormonal agent. Preclinical research has shown promising results with the use of mTOR inhibitors to overcome hormonal resistance; however, the use of this combination is investigational. Hormonal agents for grade 1 or 2 tumors with positive hormone receptor testing and endometrioid histology are an option as primary treatment in certain cases where surgery and systemic chemotherapy are contraindicated. Hormone therapies are primarily tested as secondary treatments and for recurrent tumors.

Biologics/targeted therapy:GOG 86P is investigating bevacizumab and temsirolimus in addition to cytotoxic therapy in advanced or recurrent endometrial cancer. Currently, there is little data to direct the use of these agents in endometrial carcinoma.

2. Complications of adjuvant therapy

Radiation therapy

All cytotoxic agents used for adjuvant therapy have significant toxicity profiles. The side effects of chemotherapy include: emesis, fatigue, alopecia, neutropenia, and neuropathy. TAP has grade 3-4 neutropenia rates of over 50%; thrombocytopenia, 20%; neurotoxicity, 12%; vomiting, 12%; and 2% may develop heart failure. There is little prospective data about carboplatin and paclitaxel in endometrial cancer patients; small series report grade 3-4 neutropenia rates of 36%; thrombocytopenia, 11%; neurotoxicity, 4%; and vomiting 9%. Carboplatin, cisplatin, paclitaxel, and liposomal doxorubicin can all also cause drug reactions, but these are minimized with standard pretreatment regimens.

Complications vary with modality, borders, timing, concurrent therapy, and the radiation oncologist overseeing treatment. These risks are best discussed by the individual overseeing treatment. When administered alone, EBRT and VBT have grade 3 mucous membrane and gastrointestinal complications approaching 0. However, EBRT produces significantly more GI grade 1 and 2 toxicity (approaching 50% during treatment then tends to decrease with time) while VBT has significantly more grade 1 and 2 mucosal toxicity than remains around 30%.

PORTEC-1 reported significantly more urinary urgency (45.6% vs. 31.7%, P <.001), diarrhea interfering with daily activities (25.8 vs. 14.6, P = .006), and use of incontinence products (42.6 vs. 15.2%, P <.001) at a median follow-up of 13 years. Another series of 317 women, mostly treated with EBRT and VBT together, reported 6% severe bowel late complication rates, including 6 rectovaginal fistulae and a total of 16 patients required surgery. Two percent of patients had severe bladder complications, including one vesicovaginal fistula. When given in combination with chemotherapy, the early adverse events vary with the chemotherapy regimen chosen. One series noted late grade 3-5 small or large intestinal complications of 10% to 16%.

3. Prognosis and outcome

Counseling patients regarding prognosis is a complex task due to patient factors (e.g., comorbidities, openness to adjuvant therapy, anxiety), as well as the ever-evolving combination of adjuvant therapies and alterations in the manner in which they are delivered. Given the inability to personalize statistics, when asked to provide exact numbers it is best to provide figures similar to what the patient will find when he or she searches for them using available resources. The American Cancer Society is one such resource, stating the 5-year survival rate to be approximately 90% for stage I, 70% for stage II, 50% to 60% for stage III, and 15% to 20% for stage IV. These figures are offered with preface of the inaccuracies for any given patient due to the factors above.

4. What is the evidence for specific management and treatment recommendations?